Preventing and Treating Orthostatic Hypotension: As Easy As A, B, C

REE VI W CME Educational objective: Readers will teach their patients to avoid episodes of orthostatic hypotension CREDIT Juan J. Figueroa, MD Jef f rey R. Basford, MD, PhD Philli p A. Low, MD Department of Neurology, Mayo Department of Physical Medicine and Rehabili- Department of Neurology, Mayo Clinic, Clinic, Rochester, MN tation, Mayo Clinic, Rochester, MN Rochester, MN

Preventing and treating orthostatic hypotension: As easy as A, B, C

■■Abstrt ac rthostatic hypotension is a chronic, O debilitating illness associated with com- Orthostatic hypotension is a chronic, debilitating illness mon neurologic conditions (eg, diabetic neu- that is difficult to treat. The therapeutic goal is to im- ropathy, Parkinson disease). It is common in prove postural symptoms, standing time, and function the elderly, especially in those who are institu- rather than to achieve upright normotension, which can tionalized and are using multiple medications. lead to supine hypertension. Drug therapy alone is never Treatment can be challenging, especially if the problem is neurogenic. This condition adequate. Because orthostatic stress varies with circum- has no cure, symptoms vary in different cir- stances during the day, a patient-oriented approach that cumstances, treatment is nonspecific, and ag- emphasizes education and nonpharmacologic strategies gressive treatment can lead to marked supine is critical. We provide easy-to-remember management hypertension. recommendations, using a combination of drug and non- This review focuses on the prevention and drug treatments that have proven efficacious. treatment of neurogenic causes of orthostatic hypotension. We emphasize a simple but ef- ■■Key Points fective patient-oriented approach to management, using a combination of nonpharmaco- Treatment is directed at increasing blood volume, de- logic strategies and drugs clinically proven creasing venous pooling, and increasing vasoconstriction to be efficacious. The recommendations and while minimizing supine hypertension. their rationale are organized in a practical and easy-to-remember format for both physicians Patient education and nondrug strategies alone can be and patients. effective in mild cases. Examples: consuming extra fluids and salt, wearing an abdominal binder, drinking boluses ■■ What happens when we stand up? of water, raising the head of the bed, and performing countermaneuvers and physical activity. When we stand up, the blood goes down from the chest to the distensible venous capaci- Moderate and severe cases require additional drug treat- tance system below the diaphragm. This fluid ment. Pyridostigmine (Mestinon) is helpful in moderate shift produces a decrease in venous return, ventricular filling, cardiac output, and blood cases. Fludrocortisone (Florinef) and midodrine (ProAma- pressure.1 tine) are indicated in more severe cases. This gravity-induced drop in blood pressure, detected by arterial baroreceptors in the aortic arch and carotid sinus, triggers a compensatory reflex tachycardia and vasoconstric- doi:10.3949/ccjm.77a.09118 tion that restores normotension in the upright

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position. This compensatory mechanism is be due to neuropathy (eg, diabetic or autoim- termed a baroreflex; it is mediated by affer- mune neuropathies) or to central lesions (eg, ent and efferent autonomic peripheral nerves Parkinson disease or multiple system atrophy). and is integrated in autonomic centers in the Its presence, severity, and temporal course can brainstem.2 be important clues in diagnosing Parkinson Orthostatic hypotension is the result of disease and differentiating it from other par- baroreflex failure (autonomic failure), end- kinsonian syndromes with a more ominous organ dysfunction, or volume depletion. Injury prognosis, such as multiple system atrophy to any limb of the baroreflex causes neurogenic and Lewy body dementia. orthostatic hypotension, although with affer- Nonneurogenic causes include cardiac im- ent lesions alone, the hypotension tends to be pairment (eg, from myocardial infarction or modest and accompanied by wide fluctuations aortic stenosis), reduced intravascular volume in blood pressure, including severe hyperten- (eg, from dehydration, adrenal insufficiency), sion. Drugs can produce orthostatic hypoten- and vasodilation (eg, from fever, systemic mas- sion by interfering with the autonomic path- tocytosis). ways or their target end-organs or by affecting Common drugs that cause orthostatic intravascular volume. Brain hypoperfusion, hypotension are diuretics, alpha-adrenoceptor resulting from orthostatic hypotension from blockers for prostatic hypertrophy, antihyper- any cause, can lead to symptoms of orthostatic tensive drugs, and calcium channel blockers. intolerance (eg, lightheadedness) and falls, and Insulin, levodopa, and tricyclic antidepres- if the hypotension is severe, to syncope. sants can also cause vasodilation and orthostatic hypotension in predisposed patients. ■■ A decrease of 20 MM HG Systolic Poon and Braun,6 in a retrospective study in or 10 mm Hg diastolic elderly veterans, identified hydrochlorothia- zide, lisinopril (Prinivil, Zestril), trazodone The consensus definition of orthostatic hypo- (Desyrel), furosemide (Lasix), and terazosin tension is a reduction of systolic blood pressure (Hytrin) as the most common culprits. of at least 20 mm Hg or a reduction of diastolic R ecurrent or blood pressure of at least 10 mm Hg within 3 ■■ Orthostatic hypotension unexplained minutes of erect standing.3 A transient drop is Common in the elderly that occurs with abrupt standing and resolves falls in older rapidly suggests a benign condition, such as de- The prevalence of orthostatic hypotension is adults may be a hydration, rather than autonomic failure. high in the elderly and depends on the charac- manifestation In the laboratory, patients are placed on a tilt teristics of the population studied, such as age, table in the head-up position at an angle of at use of medications, and comorbidities known of syncope due least 60 degrees to detect orthostatic changes in to be associated with this problem. Ortho- to orthostatic blood pressure. In the office, 1 minute of stand- static hypotension is more common in insti- ing probably detects nearly all cases of ortho- tutionalized elderly people (up to 68%)7 than hypotension static hypotension; however, standing beyond in those living in the community (6%).8 The 2 minutes helps establish the severity (a further high prevalence among institutionalized pa- drop in blood pressure).4 Orthostatic hypoten- tients likely reflects multiple disease processes, sion developing after 3 minutes of standing is including neurologic and cardiac conditions, uncommon and may represent a reflex presyn- as well as medications associated with ortho- cope (eg, vasovagal) or a mild or early form of static hypotension. sympathetic adrenergic dysfunction.4, 5 ■■ Clinical Manifestations are due to ■■ Neurogenic and hypoperfusion, overcompensation nonneurogenic Causes Symptoms are related to cerebral hypoperfu- Orthostatic hypotension may result from neu- sion, with resulting lack of cerebral oxygen- rogenic and nonneurogenic causes. ation (causing lightheadedness, dizziness, Neurogenic orthostatic hypotension can weakness, difficulty thinking, headache, syn-

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but subtler issues such as difficulty thinking, TABLE 1 weakness, and neck discomfort are also com- T reatment of orthostatic hypotension mon in the elderly. Recurrent or unexplained in special circumstances falls in older adults may be a manifestation of syncope due to orthostatic hypotension. O rthostatic decompensation (more severe or less responsive to pressor agents) ■■ Prognosis DEPENDS ON CAUSE Consider aggravating conditions such as anemia, hypovolemia, heart failure, deconditioning. Orthostatic hypotension is a syndrome, and Salty soups and about five 8-ounce servings of fluid over half a day, its prognosis depends on its specific cause, its if acute, or: severity, and the distribution of its autonomic Salt tablets 2 g three times a day with a minimum of eight 8-ounce and nonautonomic involvement. In patients servings of fluid over 1 day. who have extrapyramidal and cerebellar dis- Fludrocortisone (Florinef) 0.2 mg three times a day for 1 week. orders (eg, Parkinson disease, multiple system During this time, an abdominal binder can be useful. atrophy), the earlier and the more severe the involvement of the autonomic nervous sys- If severe, provide acute hospital management with intravenous tem, the poorer the prognosis.9,10 fluid expansion. In hypertensive patients with diabetes mel- Early morning orthostatic hypotension litus, the risk of death is higher if they have or- Instruct patients to: thostatic hypotension.11 Diastolic orthostatic Be careful on awakening hypotension is associated with a higher risk of Elevate the head of the bed (reducing nocturia) vascular death in older persons.12 Drink two cups of cold water 30 minutes before arising Shift from supine to an erect position in gradual stages. ■■ Management: FROM A to F Postprandial orthostatic hypotension (common in patients with diabetic neuropathy) The goal of management of orthostatic hy- Tell patients to take frequent, small meals and reduce potension is to raise the patient’s standing alcohol intake. blood pressure without also raising his or her Hot drinks, hot foods, and meals rich in carbohydrates may be supine blood pressure, and specifically to re- troublesome. duce orthostatic symptoms, increase the time the patient can stand, and improve his or her Nocturnal supine hypertension Instruct patients to: ability to perform daily activities. No specific Not take pressor medications after 6 pm treatment is currently available that achieves Elevate the head of the bed to lower intracranial blood pressure all these goals, and drugs alone are never com- Try a bedtime snack with a glass of warm fluid (to induce pletely adequate. nighttime postprandial hypotension) Therapies primarily consist of a combina- Try a glass of wine at bedtime (for vasodilator effects) tion of vasoconstrictor drugs, volume expan- Remove abdominal binder before bedtime. sion, compression garments, and postural ad- Anemia in orthostatic hypotension justment. Education about orthostatic stressors (can exacerbate symptoms) and warning symptoms empowers the patient to adopt easy lifestyle changes to minimize and Mild to moderate normocytic normochronic anemia is not uncommon. handle orthostatic stress. Consider erythropoietin (Epogen, Procrit) 50 units/kg Because the mainstays of treatment are subcutaneously three times a week (monitor reticulocytes and 38 volume expansion and vasoconstriction, it is hematocrit). difficult to improve the symptoms of orthostatic hypotension without inducing some degree of supine hypertension. Strategies to cope, or feeling faint) and a compensatory minimize nocturnal hypertension and to treat autonomic overreaction (causing palpitations, orthostatic hypotension in special circum- tremulousness, nausea, coldness of extremi- stances are summarized in Table 1. ties, chest pain, and syncope). Treatment should always start with identi- Lightheadedness is a common symptom, fying and, if possible, reducing or discontinu-

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TABLE 2 S ome drugs that may decrease blood pressure or exacerbate orthostatic hypotension

CLASS E XAMPles

N arcotics Morphine Tricyclic antidepressants Imipramine (Tofranil) Nontricyclic antidepressants Trazodone (Desyrel), paroxetine (Paxil), venlafaxine (Effexor) Monoamine oxidase inhibitors Phenelzine (Nardil) Neuroleptics Chlorpromazine (Thorazine), quetiapine (Seroquel) Antihypertensive agents Clonidine (Catapres), labetalol (Normodyne, Trandate), verapamil (Calan, Isoptin, Verelan), captopril (Capoten), hydralazine (Apresoline) Nitrates Diuretics Furosemide (Lasix) Antiparkinsonian agents Levodopa (Sinemet), bromocriptine (Parlodel), ropinirole (Requip), pramipexole (Mirapex) Drugs for prostatism Prazosin (Minipress), terazosin (Hytrin) Drugs for erectile dysfunction Sildenafil (Viagra) Drugs that induce autonomic Amiodarone (Cordarone, Pacerone), vincristine (Oncovin, Vincasar), neuropathy cisplatin (Platinol) Insulin (in diabetic patients with autonomic failure) I t is difficult to improve ing drugs that may be causing or exacerbating vasoconstrictor effect only during standing, the symptoms the problem (Table 2). Similarly, conditions but because its effect is modest it should be of orthostatic 13 that may exacerbate it (eg, anemia ) should used in mild orthostatic hypotension that does hypotension be identified and minimized Table( 3). not improve with nonpharmacologic mea- Nonpharmacologic interventions should sures and in moderate cases. Its effect can be caused by then be considered. They can be tried in any enhanced with additional low doses of mido- autonomic order or combination based on the patient’s drine (ProAmatine). Midodrine with or with- convenience or safety. They work by expand- out fludrocortisone should be used in severe failure without ing blood volume (taking in extra fluid and orthostatic hypotension. inducing some salt), decreasing nocturia (raising the head of We use an A-to-F mnemonic to highlight degree of the bed), decreasing venous pooling (wearing management strategies (see below and T Able an abdominal binder, performing counterma- 4). The alphabetic order is not meant to rep- supine neuvers, engaging in physical activity), or in- resent a sequential approach to management, hypertension ducing a pressor response (drinking a bolus of but rather to facilitate consideration of all the cold water). available treatments. If hypovolemia is playing a major role, and the patient cannot ingest enough salt or plas- A: Abdominal compression ma volume fails to increase despite salt supple- In conditions in which there is adrenergic de- mentation, fludrocortisone (Florinef) should nervation of vascular beds, there is an increase be considered. Untreated hypovolemia will in vascular capacitance and peripheral venous decrease the efficacy of vasoconstrictor drugs. pooling. Compression of capacitance beds (ie, Pyridostigmine (Mestinon) has a putative the legs and abdomen) improves orthostatic

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ing violent aircraft maneuvers) inflated to 20 TABLE 3 mm Hg—an increase of about 17/8 mm Hg. C onditions that can decrease Higher gravity-suit pressures had a greater ef- blood pressure or exacerbate fect. orthostatic hypotension In practical terms, the binder should be tight enough to exert gentle pressure. It Dehydration should be put on before rising from bed in Time of day (early morning after nocturnal diuresis) the morning and taken off when lying supine, to avoid supine hypertension. Advantages Rising quickly after prolonged sitting or recum- are that a binder’s effects are immediate, its bency benefits can be easily assessed, and it can be Prolonged motionless standing used on an as-needed basis by patients who need it only during periods of prolonged or- Physical exertion, especially vigorous or isometric exercise thostatic stress. Binders are also easy to fit and are available in most sporting good stores and Alcohol ingestion on the Web (try searching for “abdominal Carbohydrate-heavy meals binder”). When abdominal compression alone is not Heat exposure or fever enough, the addition of compression of the Straining during micturition or defecation lower extremities can result in further benefits. This can be achieved by using compression garments that ideally extend to the waist symptoms.14 The improvement is due to a re- or, at the least, to the proximal thigh. duction of venous capacitance and an increase in total peripheral resistance.14 B: Boluses of water On standing, healthy adults experience an Rapidly drinking two 8-oz (500-mL) glasses orthostatic shift of approximately 500 mL of of cold water helps expand plasma volume. It S tart by blood to the lower extremities15 that, when also, within a few minutes, elicits a significant identifying added to an increased vascular capacitance in pressor effect that is in part norepinephrine- those with orthostatic hypotension, results in mediated,18,19 increasing the standing systolic and, if possible, a relative state of hypovolemia. blood pressure by more than 20 mm Hg for reducing or Compression of the legs alone is not as about 2 hours and improving symptoms and 18,20 discontinuing beneficial as compression of the abdomen orthostatic endurance. This easy tech- because the venous capacitance of the calves nique can be used when prolonged standing is drugs that may and thighs is relatively small compared with expected (eg, shopping). be causing or that of the splanchnic mesenteric bed, which accounts for 20% to 30% of total blood vol- B (continued): Bed up exacerbating ume.16 Moreover, compression garments and The head of the bed of a patient with ortho- the problem stockings that are strong enough to produce a static hypotension should be elevated by 10 to measurable effect on orthostatic hypotension 20 degrees or 4 inches (10 cm) to decrease noc- are cumbersome to put on and uncomfort- turnal hypertension and nocturnal diuresis.21 able to wear. Because some patients gain sig- During the day, adequate orthostatic stress, nificant benefit from abdominal compression ie, upright activity, should be maintained. If alone, this should be considered the first step patients are repeatedly tilted up, their ortho- in reducing venous capacitance. static hypotension is gradually attenuated, In a laboratory experiment, Smit et al17 presumably by increasing venomotor tone.22 found that an elastic abdominal binder that exerted 15 to 20 mm Hg of pressure on the C : Countermaneuvers abdomen raised the standing blood pressure Physical countermaneuvers involve isometri- by about 11/6 mmHg, which was comparable cally contracting the muscles below the waist to the effect of a gravity suit (such as those for about 30 seconds at a time, which reduces worn by fighter pilots to prevent syncope dur- venous capacitance, increases total peripheral

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resistance, and augments venous return to the TABLE 4 heart.23,24 These countermeasures can help maintain blood pressure during daily activities R ecommendations for patients and should be considered at the first symptoms with orthostatic hypotension: of orthostatic intolerance and in situations of From A to F orthostatic stress (eg, standing for prolonged periods). Your physician has determined that you have orthostatic hypotension. Specific techniques include23: This means that your blood pressure drops when you stand up, making • Toe-raising you feel dizzy or perhaps even pass out. The following may help. • Leg-crossing and contraction A: Abdominal compression • Thigh muscle co-contraction Wear an abdominal binder when out of bed. • Bending at the waist B: Bolus of water • Slow marching in place On bad days, drink two 8-ounce glasses of cold water prior • Leg elevation. to prolonged standing. D: Drugs B (continued): Bed up Midodrine, a vasopressor, is effective and Sleep with the head of the bed elevated 4 inches. safe when used for treating neurogenic ortho- C: Countermaneuvers static hypotension.25 It has been shown to in- Contract the muscles below your waist for about half a minute at crease standing systolic blood pressure, reduce a time to raise your blood pressure during prolonged standing or orthostatic lightheadedness, and increase when you become symptomatic. standing and walking time. D: Drugs A common starting dose is 5 mg three Drugs such as midodrine (ProAmatine), pyridostigmine (Mestinon), and times a day; most patients respond best to 10 fludrocortisone (Florinef) can be used to raise your blood pressure. mg three times a day. As its duration of action Recognize that some drugs you take can lower blood pressure. is short (2 to 4 hours),25–27 it should be taken before arising in the morning, before lunch, E: Education and in the midafternoon. To avoid nocturnal Recognize symptoms that indicate your standing blood pressure is supine hypertension, doses should not be tak- falling. en after the midafternoon, and a dose should Recognize the conditions that lower blood pressure, such as a be omitted if the supine or sitting blood pres- heavy meal, positional changes, heat, exercise, or a hot bath. sure is greater than 180/100 mm Hg. Learn the things you can do to raise your blood pressure. Midodrine’s main side effects are supine hypertension, scalp paresthesias, and pilomo- E (continued): Exercise tor reactions (goosebumps). Vasoconstrictors Avoid inactivity and consider a gentle exercise program. such as midodrine are ineffective when plasma F: Fluids and salt volume is reduced. You need plenty of salt and fluids. Fludrocortisone is a synthetic mineralocorticoid that has a pressor effect as a result of its ability to expand plasma volume and panded adequately. However, in view of these increase vascular alpha-adrenoceptor sensitiv- effects, fludrocortisone is contraindicated in ity.28–30 This medication is helpful when plas- congestive heart failure and chronic renal ma volume fails to adequately increase with failure. The potential risks are severe hypo- salt supplementation31 and for patients who kalemia and excessive supine hypertension. cannot ingest enough salt or do not respond Frequent monitoring of serum potassium, a adequately to midodrine. diet high in potassium, and regular checks of The usual dose is 0.1 to 0.2 mg/day, but it supine blood pressure are advised, especially may be increased to 0.4 to 0.6 mg/day in pa- at higher doses, when added to midodrine, or tients with refractory orthostatic hypotension. in elderly patients who tend to poorly tolerate If the patient gains 3 to 5 pounds (1.2–2.3 the medication.28,29,32 kg) and develops mild dependent edema, Pyridostigmine is a cholinesterase inhibi- you can infer that the plasma volume has ex- tor that improves ganglionic neurotransmis-

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sion in the sympathetic baroreflex pathway. potension related to nocturnal diuresis and Because this pathway is activated primarily arising from bed, physical activity sufficient to during standing, this drug improves orthostat- cause muscle vasodilation, heat exposure (eg, ic hypotension and total peripheral resistance hot weather or a hot bath or shower) produc- without aggravating supine hypertension. Be- ing skin vessel vasodilation, sudden postural cause the pressor effect is modest, it is most changes, and prolonged recumbency. Once adequate for patients with mild to moderate these stressors are explained, patients have no orthostatic hypotension.33,34 difficulty recognizing them. Dosing is started at 30 mg two to three The patient should also be instructed in times a day and is gradually increased to 60 how to manage situations of increased ortho- mg three times a day. The drug’s effectiveness static stress and periods of orthostatic decom- can be enhanced by combining each dose of pensation, to minimize nocturnal hyperten- pyridostigmine with 5 mg of midodrine with- sion, and to modify their activities of daily out occurrence of supine hypertension.34 Mes- living. Keeping a log of supine and upright tinon Timespan, a 180-mg slow-release pyrid- blood pressures (taken with an automated ostigmine tablet, can be taken once a day and sphygmomanometer) during situations of or- may be a convenient alternative. thostatic stress can help establish whether The main side effects are cholinergic (ab- worsening symptoms are related to orthostatic dominal colic, diarrhea). hypotension or to another mechanism. Once Review the patient’s medications. If he patients discover that they can actively deal or she is taking any drug that may cause or- with these situations, they develop a great thostatic hypotension, consider discontinuing sense of empowerment. it, substituting another drug, or changing the dosage (Table 2). In the elderly, antiparkinso- E (continued): Exercise nian, nitrate, antidepressant, diuretic, pros- Mild physical exercise improves orthostatic tate, and antihypertensive medications35 may tolerance by reducing venous pooling and be particularly suspect. increasing plasma volume.36 Deconditioning Fludrocortisone from lack of exercise exacerbates orthostatic helps when E: Education hypotension.37 Because upright exercise may Education is probably the single most impor- increase the orthostatic drop in blood pres- plasma volume tant factor in the proper control of orthostatic sure, training in a supine or sitting position does not hypotension. A number of issues should be (eg, swimming, recumbent biking) is advis- increase considered. able. Isotonic exercise (eg, light weight-lift- • Patients should be taught, in simple terms, ing) is recommended because the incorrect with salt the mechanisms that maintain postural straining and breath-holding during isometric supplements normotension and how to recognize the exercise (eg, holding weights in the same posi- onset of orthostatic symptoms. tion) may decrease venous return. • They must realize that there is no specific treatment of the underlying cause and that F: Fluid and salt (volume expansion) drug treatment alone is not adequate. Maintaining an adequate plasma volume is cru- • They should be taught nonpharmacologic cial. Patients should drink five to eight 8-ounce approaches and be aware that other drugs glasses (1.25 to 2.5 L) of water or other fluid per they start may worsen symptoms. day. Many elderly people do not take in this It is also important that the patient learn much. The patient should have at least 1 glass the conditions (and their mechanisms) that or cup of fluid with meals and at least twice at can lower blood pressure (Table 3). Such condi- other times of each day to obtain 1 L/day. tions include prolonged or motionless stand- Salt intake should be between 150 and 250 ing, alcohol ingestion (causing vasodilation), mmol of sodium (10 to 20 g of salt) per day. carbohydrate-heavy meals (causing postpran- Sodium helps with retention of ingested fluids dial orthostatic hypotension related to an in- and should be maximized if tolerated. How- crease in the splanchnic-mesenteric venous ever, caution should be exercised in patients capacitance), early morning orthostatic hy- who have severe refractory supine hyperten-

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sion, uncontrolled hypertension, or comorbid- fluid intake leading to an adequate volume ities characterized by insterstitial edema (eg, expansion can be verified by checking the heart failure, liver failure). Some patients are 24-hour urinary sodium content: patients very sensitive to sodium supplementation and who excrete less than 170 mmol can be can fine-tune their orthostatic control with treated with 1 to 2 g of supplemental sodium salt alone. If salting food is not desired, pre- three times a day.38 pared soups, pretzels, potato chips, and 0.5- or 1.0-g salt tablets can be an option. ■■ Acknowledgments Patients need to maintain a high-potassium diet, as the high sodium intake combined This work was supported in part by the Na- with fludrocortisone promotes potassium loss. tional Institutes of Health (NS 32352, NS Fruits (especially bananas) and vegetables 44233, NS 22352, NS 43364), Mayo CTSA have high potassium content. (UL1 RR24150), and Mayo Funds. The con- The combination of fludrocortisone and a tent is solely the responsibility of the authors high-salt diet can also cause sustained supine and does not necessarily represent the official hypertension, which can be minimized by the views of the National Institute of Neurological interventions noted in Table 2. Disorders and Stroke or the National Institutes Appropriate salt supplementation and of Health. ■

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ADDRESS: Phillip A. Low, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; e-mail [email protected].

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